A major aim of this application is to identify causes of the toxic effects that appear immediately or at prolonged periods of time after phencyclidine (PCP) use. There has been considerable speculation that mobilization of PCP from storage sites may play a role in delayed toxicity. We plan to continue our studies of tissue sequestration of PCP and, more importantly, PCP metabolites in acutely and chronically-treated animals. Due to the fact that PCP is most commonly abused by smoking, emphasis will be placed upon identification of PCP pyrolysis products and quantitation of their delivery in smoke. Cigarettes containing PCP radiolabeled in the phenyl and piperidine moieties will be 'smoked' so that the pyrolysis products can be isolated. Following identification of all major pyrolysis products, mice will be exposed to smoke from these cigarettes in order to study the long-term biodisposition of PCP, its pyrolysis products and their metabolites. We will also examine the possibility that some of the adverse effects of PCP arise from smoking piperidinocyclohexanecarbonitrile (PCC), a frequent contaminant of PCP. Pyrolysis studies will allow us to estimate the quantity of PCC and cyanide that smokers are being exposed to. Emergency treatment of PCP abusers is usually carried out to reverse CNS effects ranging from extremely bizarre behavior to coma. Although treatments frequently includes urine acidification, there is no direct evidence that this procedure significantly alters brain levels of PCP. We propose to evaluate the effectiveness of urine acidification for altering the biodisposition of PCP in rats with particular emphasis on brain levels. The effectiveness of charcoal and cholestyramine to retard absorption of PCP from the gastrointestinal tract will also be evaluated. A combination of treatments may prove to be more efficacious than a single treatment. The last objective is to identify areas of the rat brain upon which PCP produces its behavioral effects. We plan to correlate the behavioral effects (drug discrimination) to the biodisposition of PCP in both tolerant and nontolerant rats as well as after administration of PCP intraventricularly and into specific brain sites. The research proposed in this application will enable us to better understand the toxic manifestations of PCP abuse and will provide assistance in developing a rational treatment for these clinical problems.